Buprenorphine, a semi-synthetic opiate classified as a “partial agonist” behaves very much like classical mu agonists such as morphine, exerting an analgesic effect through high affinity binding to mu subclass opiate receptors in the central nervous system.
Buprenorphine has been used as an analgesic for treatment of moderate to severe pain in postoperative cancer patients. Therapeutic doses administered by intravenous and intramuscular routes range from 0.3 to 0.6 mg. Buprenorphine produces effects similar to morphine but is 25-40 times more potent and has a large therapeutic index. Buprenorphine stimulates the mu opiate receptors in the brain and produces effects associated with other mu agonists such as morphine. Such effects include analgesia, euphoria, sedation, and respiratory depression. For this reason, oral buprenorphine formulations have the potential for misuse (i.e., diversion for recreational, rather than therapeutic, purposes), making them unsuitable for use as a take-home medication.
Many patients with chronic pain require long-term continuous dosing with opiate analgesics. Effective treatment often necessitates the ingestion of multiple tablets per day. Compliance with this dosing scheme is often poor. Further, enteral drug delivery is poorly tolerated or prohibited in patients with particular indications, such as some patients with cancer-related pain in whom continuous drug delivery is a necessity. However, continuous parenteral delivery of opiate analgesics is expensive, cumbersome, and dependent upon the availability of refrigeration, catheters, pumps, and trained personnel. Further, concerns over drug diversion for illicit use often limits availability of opiate analgesics. An oral tablet containing a combination of buprenorphine and naloxone, an opiate receptor antagonist, has been developed to address this issue (see, e.g., U.S. Pat. No. 4,935,428). If an opiate addict attempts to abuse the combination tablet by dissolving it and injecting it intravenously, unpleasant withdrawal symptoms brought on by the naloxone component will result. However, opiate antagonists such as naloxone may reduce the analgesic effectiveness of buprenorphine to those who are using it therapeutically for pain relief and such antagonists may cause undesirable side effects. Thus, there is a need for an improved buprenorphine formulation which is administrable to those in need of analgesia but which provides a lower potential for abuse.
Buprenorphine has also been studied as a treatment for addiction to heroin and other opiates. Opiate addiction is a major societal problem throughout the world. The general treatment program for such addiction includes incorporation of a drug substitute, e.g., methadone, into an oral formulation for administration to the drug addict. Typically, such drug substitutes function by binding to receptors specific for the drug of abuse. The effectiveness of such treatment depends largely upon adherence to an established treatment schedule. Often, poor compliance with dosing regimens complicates treatment. Further, the cost of such therapy is significant, a large portion of the cost relating to frequent clinic visits and the monitoring of urine tests to assure compliance with drug dosing, as well as pharmacy charges relating to dispensing of methadone. Another problem with oral dosage forms such as powders or tablets is that they can be dissolved in water and concentrated to provide a solution which may be injected by the addict in lieu of the drug of abuse. A means for long-term continuous administration of a drug suitable for treatment of opiate dependency in a form that is not subject to potential abuse, would significantly reduce the compliance problems encountered in drug addiction treatment programs.
Buprenorphine's unique effects and pharmacology make it a clinically attractive treatment option for opiate dependency. For example, buprenorphine produces less euphoria than morphine and heroin. When compared with other opiates, it also causes a significantly lower degree of sedation. Further, direct dependence studies have shown little physical dependence upon withdrawal of the drug.
There is a need for a buprenorphine formulation, suitable for long-term, continuous administration, that will improve compliance for both pain relief and drug dependency treatment regimens. There is also a need for a buprenorphine formulation that will reduce abuse potential, and in which the addition of an antagonist such as naloxone will not be necessary.